EC Expands SC Daratumumab’s Indication for Use in All Transplant Eligibility Settings in Newly Diagnosed Myeloma

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The European Commission (EC) has expanded the indication for the subcutaneous (SC) formulation of daratumumab (Darzalex) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) to include the treatment of adult patients with newly diagnosed multiple myeloma, regardless of transplant eligibility status.1

This regulatory decision marks an expansion from the EC’s October 2024 approval that authorized the use of SC daratumumab plus VRd exclusively for patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplant (ASCT). The October approval was supported by data the phase 3 PERSEUS study (NCT03710603).

The expanded approval to include patients ineligible for ASCT was based on data from the the phase 3 CEPHEUS trial (NCT03652064), which showed that at a median follow-up of 58.7 months (range, 0.1-64.7), patients treated with daratumumab plus VRd (n = 197) achieved an minimal residual disease (MRD)–negativity at a sensitivity of 10-5 with a complete response (CR) or better at a rate of 60.9% vs 39.4% for those given VRd (n = 198; odds ratio [OR], 2.37; 95% CI, 1.58-3.55; P < .0001).3

"Daratumumab has become a cornerstone of multiple myeloma treatment over the past decade and is now the only anti-CD38 antibody approved to treat all patient types in the frontline setting, regardless of transplant eligibility,” Edmond Chan, MBChB, MD, EMEA Therapeutic Area Lead Haematology, Johnson & Johnson Innovative Medicine, explained in a news release.1 “This latest approval confirms the enhanced benefit of [subcutaneous] daratumumab–based quadruplet regimens and its versatility and effectiveness in addressing the diverse needs of those affected by this complex disease."

CEPHEUS Trial Design

CEPHEUS was an international, randomized, open-label study designed to evaluate the efficacy and safety of subcutaneous daratumumab in combination VRd compared with standard VRd in patients who were at least 18 years of age with histologically confirmed newly diagnosed multiple myeloma and were either ineligible for ASCT or did not have ASCT planned as part of initial therapy.2 Key eligibility criteria included adequate organ function and measurable disease. Patients with prior exposure to CD38-targeted therapies, proteasome inhibitors, or immunomodulatory agents, as well as those with active infections, uncontrolled comorbidities, or concurrent malignancies, were excluded.

Patients were randomly assigned to receive either daratumumab plus VRd or VRd alone. Daratumumab was administered subcutaneously following the approved dosing schedule. Both treatment arms received VRd in standard 21-day cycles.

The primary end point was the overall MRD negativity rate. Secondary end points included sustained MRD negativity for greater than 12 months, CR or better rate, progression-free survival (PFS), and overall survival (OS). Safety assessments were conducted regularly, including adverse effect (AE) monitoring, laboratory evaluations, and imaging.

CEPHEUS Efficacy and Safety Findings Continued

The proportion of patients achieving sustained MRD negativity for more than 12 months was 48.7% in the daratumumab plus VRd arm compared with 26.3% in the VRd arm (OR, 2.63; 95% CI, 1.73–4.00; P < .0001). The subcutaneous daratumumab–based quadruplet regimen also led to a CR or better rate of 81.2% vs 61.6% for VRd alone (OR, 2.73; 95% CI, 1.71–4.34; P < .0001). Additionally, treatment with daratumumab VRd reduced the risk of disease progression or death by 43% compared with VRd (HR, 0.57; 95% CI, 0.41–0.79; P < .0005). Median PFS was not reached in the daratumumab plus VRd arm vs 52.6 months in the VRd arm. OS data remained immature.

The safety profile of daratumumab plus VRd was consistent with the established safety profiles of subcutaneous daratumumab and VRd. Grade 3/4 hematologic and non-hematologic AEs occurring in more than 10% of patients in the daratumumab plus VRd vs VRd arms included neutropenia (44.2% vs 29.7%), thrombocytopenia (28.4% vs 20.0%), anemia (13.2% vs 11.8%), peripheral neuropathy (8.1% vs 8.2%), diarrhea (12.2% vs 9.2%), and COVID-19 infection (11.2% vs 4.6%)

“At Johnson & Johnson, our dedication to advance multiple myeloma research spans more than 20 years and our commitment to transforming outcomes for patients has never been stronger than it is today,” Jordan Schecter, MD, vice president, Disease Area leader, Multiple Myeloma, Johnson & Johnson Innovative Medicine, added in a news release.1 “This landmark approval enables us to offer all patient populations access regardless of age, fitness or risk to a daratumumab-based triplet or quadruplet regimen in the frontline setting – a critical step towards our ultimate goal of delivering a functional cure.”

References

1. European Commission approves Johnson & Johnson’s subcutaneous DARZALEX (daratumumab)-based quadruplet regimen for the treatment of patients with newly diagnosed multiple myeloma, regardless of transplant eligibility. News Release. Johnson and Johnson. April 7, 2025. Accessed April 7, 2025. https://www.jnj.com/media-center/press-releases/european-commission-approves-johnson-johnsons-subcutaneous-darzalex-daratumumab-based-quadruplet-regimen-for-the-treatment-of-patients-with-newly-diagnosed-multiple-myeloma-regardless-of-transplant-eligibility
2. Darzalex (daratumumab)-SC based quadruplet regimen approved by the European Commission for patients with newly diagnosed multiple myeloma who are transplant-eligible. News release. Janssen-Cilag International NV. October 23, 2024. Accessed April 7, 2025. https://innovativemedicine.jnj.com/newsroom/oncology/darzalex-daratumumab-sc-based-quadruplet-regimen-approved-by-the-european-commission-for-patients-with-newly-diagnosed-multiple-myeloma-who-are-transplant-eligible
3. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nat Med. Published online February 5, 2025. doi:10.1038/s41591-024-03485-7